Agrimonia eupatoria L. (AE) has a rich tradition of use in wound healing improvement across various cultures worldwide. In previous studies, we revealed that Agrimonia eupatoria L. water extract (AE) possesses a rich polyphenolic composition, displaying remarkable antioxidant properties. Our investigations also demonstrated that lipophosphonoxin (LPPO) exhibited antibacterial efficacy in vitro while preserving the proliferation and differentiation of fibroblasts and keratinocytes. Building upon our prior findings, in this study, we intended to examine whether a combination of AE and LPPO could enhance skin wound healing while retaining antibacterial attributes. The antibacterial activity of AE/LPPO against Staphylococcus aureus was evaluated, alongside its effects on fibroblast-to-myofibroblast transition, the formation of extracellular matrix (ECM), and endothelial cells and keratinocyte proliferation/phenotype. We also investigated AE/LPPO's impact on TGF-β1 and VEGF-A signaling in keratinocytes/fibroblasts and endothelial cells, respectively. Additionally, wound healing progression in rats was examined through macroscopic observation and histological analysis. Our results indicate that AE/LPPO promotes myofibroblast-like phenotypic changes and augments ECM deposition. Clinically relevant, the AE/LPPO did not disrupt TGF-β1 and VEGF-A signaling and accelerated wound closure in rats. Notably, while AE and LPPO individually exhibited antibacterial activity, their combination did not lead to synergism, rather decreasing antibacterial activity, warranting further examination. These findings underscore substantial wound healing improvement facilitated by AE/LPPO, requiring further exploration in animal models closer to human physiology.

• Keywords
• extracellular matrix, phytotherapy, regeneration, repair, skin tissue,
• MeSH
• Agrimonia * chemistry   MeSH
• Anti-Bacterial Agents * pharmacology   chemistry   MeSH
• Fibroblasts drug effects   metabolism   MeSH
• Wound Healing * drug effects   MeSH
• Keratinocytes drug effects   MeSH
• Rats MeSH
• Humans MeSH
• Rats, Sprague-Dawley MeSH
• Cell Proliferation drug effects   MeSH
• Plant Extracts * pharmacology   chemistry   MeSH
• Staphylococcus aureus * drug effects   MeSH
• Transforming Growth Factor beta1 metabolism   MeSH
• Vascular Endothelial Growth Factor A metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents * MeSH
• Plant Extracts * MeSH
• Transforming Growth Factor beta1 MeSH
• Vascular Endothelial Growth Factor A MeSH

Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding β-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension. Here, we present the synthesis of novel hydrophilic glycopolymer inhibitors of Gal-3 based on a polyoxazoline chain decorated with carbohydrate ligands. Biolayer interferometry revealed a high binding affinity of these glycopolymers to Gal-3 in the subnanomolar range. In the cell cultures of cardiac fibroblasts and pulmonary artery smooth muscle cells, the most potent glycopolymer 18 (Lac-high) caused a decrease in the expression of markers of tissue remodeling in pulmonary hypertension. The glycopolymers were shown to penetrate into the cells. In a biodistribution and pharmacokinetics study in rats, the glycopolymers accumulated in heart and lung tissues, which are most affected by pulmonary hypertension.

• MeSH
• Pulmonary Artery drug effects   metabolism   MeSH
• Biomarkers MeSH
• Fibroblasts drug effects   metabolism   MeSH
• Galectin 3 * antagonists & inhibitors   metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Hypertension, Pulmonary * drug therapy   metabolism   MeSH
• Polymers chemistry   pharmacology   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• Galectin 3 * MeSH
• Polymers MeSH

BACKGROUND/AIM: We have previously shown that the water extract of Agrimonia eupatoria L. (AE) is a valuable source of polyphenols with excellent antioxidant properties and has clinical potential for the prevention and/or adjuvant therapy of cardiovascular complications associated with diabetes. Inspired by our previously published data, in the present study we examined whether AE improves skin wound healing in a series of in vitro and in vivo experiments. MATERIALS AND METHODS: In detail, we investigated the ability of the AE extract to induce fibroblast to myofibroblast conversion, extracellular matrix (ECM) deposition, and keratinocyte proliferation/differentiation, in vitro. In parallel, in an animal model, we measured wound tensile strength (TS) and assessed the progression of open wounds using basic histology and immunofluorescence. RESULTS: The AE extract induced the myofibroblast-like phenotype and enhanced ECM deposition, both in vitro and in vivo. Furthermore, the wound TS of skin incisions and the contraction rates of open excisions were significantly increased in the AE-treated group. CONCLUSION: The present data show that AE water extract significantly improves the healing of open and sutured skin wounds. Therefore, our data warrant further testing in animal models that are physiologically and evolutionarily closer to humans.

• Keywords
• Skin tissue, extracellular matrix, phytotherapy, regeneration, repair,
• MeSH
• Agrimonia * MeSH
• Fibroblasts MeSH
• Wound Healing MeSH
• Keratinocytes MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Plant Extracts pharmacology   MeSH
• Water MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Plant Extracts MeSH
• Water MeSH

Active wound dressings are attracting extensive attention in soft tissue repair and regeneration, including bacteria-infected skin wound healing. As the wide use of antibiotics leads to drug resistance we present here a new concept of wound dressings based on the polycaprolactone nanofiber scaffold (NANO) releasing second generation lipophosphonoxin (LPPO) as antibacterial agent. Firstly, we demonstrated in vitro that LPPO released from NANO exerted antibacterial activity while not impairing proliferation/differentiation of fibroblasts and keratinocytes. Secondly, using a mouse model we showed that NANO loaded with LPPO significantly reduced the Staphylococcus aureus counts in infected wounds as evaluated 7 days post-surgery. Furthermore, the rate of degradation and subsequent LPPO release in infected wounds was also facilitated by lytic enzymes secreted by inoculated bacteria. Finally, LPPO displayed negligible to no systemic absorption. In conclusion, the composite antibacterial NANO-LPPO-based dressing reduces the bacterial load and promotes skin repair, with the potential to treat wounds in clinical settings.

• MeSH
• Anti-Bacterial Agents administration & dosage   therapeutic use   MeSH
• Wound Healing drug effects   MeSH
• Wound Infection drug therapy   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Nanofibers * MeSH
• Bandages * MeSH
• Staphylococcal Infections drug therapy   MeSH
• Staphylococcus aureus * MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH